Developmental Biology - Aging|
Linking Aging and RNA-binding Proteins
Inability to eliminate defective mitochondria ages tissues...
As we age, our bodies undergo biological changes causing disfunction in our cells and by consequence, our tissues. However, most studies focus only on mechanisms based on mRNA transcription, important in gene expression (function), but only part of the complex regulatory mechanisms in our cells.
Scientists led by Johan Auwerx's lab at EPFL (Ecole Polytechnique Federale de Lausanne), have taken a different route, studing the link between aging and RNA-binding proteins (RBPs) that bind mRNA molecules and regulate their fate after gene transcription. The findings appear in Molecular Cell.
The scientists first screened cells from old animals to identify RBPs that change with aging. This revealed that one particular protein, Pumilio2 (PUM2), is highly induced in old animals.
Pumilio2 binds to mRNA molecules containing specific recognition sites and represses translation of the targeted mRNAs into proteins.
Using a systems genetics approach, researchers identified a new mRNA target to which PUM2 binds. This mRNA encodes for a protein called Mitochondrial Fission Factor (MFF), a pivotal regulator of mitochondrial fission - by which mitochondria are broken up into smaller mitochondria.
Having high levels of MFF allows for the clearance of broken up, dysfunctional mitochondria, a process called mitophagy. This newly identified PUM2/MFF axis becomes dysregulated with aging.
Evidence for the PUM2/MFF process came from examining muscle and brain tissues of old animals to find increased PUM2. Fewer MFF proteins reduces mitochondrial fission and mitophagy. Unable to chop up defective mitochondria into smaller bits for removal, they accumulate as unhealthy organelles disrupting cellular functions.
However, removing PUM2 from the muscles of old mice can reverse this process.
"We used the CRISPR-Cas9 technology to specifically target and inactivate the gene encoding for Pum2 in the gastrocnemius muscles of old rodents," says Davide D'Amico, first author of the paper. "Reducing Pum2 levels, we obtained more MFF protein and increased mitochondrial fragmentation and mitophagy. Notably, the consequence was a significant improvement of the mitochondrial function in older animals."
The same mechanism is conserved across species in the nematode C. elegans, a microscopic worm, where the protein PUF-8 is also induced with aging.
"Depleting the gene for PUF-8 from old worms is sufficient to improve mitochondrial function and to increase lifespan," says Johan Auwerx. "This work is an example of how a multi-omics and cross-species approach can unveil new genes associated with aging."
RNA-binding proteins are also linked to neuromuscular degenerative diseases — such as Amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease, Multiple sclerosis, Muscular dystrophy and many more — and often aggregate in pathological granules.
"We discovered PUM2 tends to condense into particles that bind and trap Mff mRNA with aging. These observations require further study, but clearly show RNA-binding proteins could be promising targets in aging and age-related dysfunctions."
Davide D’Amico PhD, Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland
• PUM2, and its ortholog in C. elegans, PUF-8, are upregulated upon aging
• PUM2 represses Mff translation and impairs mitochondrial fission
• The PUM2/MFF axis regulates mitophagy and mitochondrial function
• Depletion of puf-8 and Pum2 in old worms and mice improves mitochondrial homeostasis
Little information is available about how post-transcriptional mechanisms regulate the aging process. Here, we show that the RNA-binding protein Pumilio2 (PUM2), which is a translation repressor, is induced upon aging and acts as a negative regulator of lifespan and mitochondrial homeostasis. Multi-omics and cross-species analyses of PUM2 function show that it inhibits the translation of the mRNA encoding for the mitochondrial fission factor ( Mff), thereby impairing mitochondrial fission and mitophagy. This mechanism is conserved in C. elegans by the PUM2 ortholog PUF-8. puf-8 knock-down in old nematodes and Pum2 CRISPR/Cas9-mediated knockout in the muscles of elderly mice enhances mitochondrial fission and mitophagy in both models, hence improving mitochondrial quality control and tissue homeostasis. Our data reveal how a PUM2-mediated layer of post-transcriptional regulation links altered Mff translation to mitochondrial dynamics and mitophagy, thereby mediating age-related mitochondrial dysfunctions.
Davide D’Amico, Adrienne Mottis, Francesca Potenza, Vincenzo Sorrentino,Hao Li, Mario Romani, Vera Lemos, Kristina Schoonjans, Nicola Zamboni, Graham Knott, Bernard L. Schneider and Johan Auwerx.br>
EPFL Laboratory of Metabolic Signaling, Institute of Bioengineering
EPFL Brain Mind Institute
ETZH Department of Biology, Institute of Molecular Systems Biology
EPFL Proteomics Core Facility
EPFL Histology Core Facility
EPFL BioEM Facility
Davide D'Amico, Adrienne Mottis, Francesca Potenza, Vincenzo Sorrentino, Hao Li, Mario Romani, Vera Lemos, Kristina Schoonjans, Nicola Zamboni, Graham Knott, Bernard L. Schneider, Johan Auwerx. The RNA-binding protein PUM2 impairs mitochondrial dynamics and mitophagy during aging. Molecular Cell 10 January 2019. DOI: 10.1016/j.molcel.2018.11.034
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PUM2 binds to mRNA to create a protein called Mitochondrial Fission Factor (MFF) which clears a cell of defective mitochondria. Imbalance in PUM2/MFF litters a cell with defective mitochondria.